Delivery device for zero-order release of an active principle into a dissolution fluid and process for its preparation

ABSTRACT

A delivery device for zero-order release of an active principle into a dissolution fluid includes a reservoir consisting of a solid matrix of a homogeneous mixture of a polymer material, at least a portion of the active principle and an additive soluble in the dissolution fluid with negative heat of solution, a coating on the solid matrix-type reservoir of a first, release rate-controlling insoluble membrane which modulates the active principle release according to the desired kinetics; and a second, protective membrane on the release rate-controlling membrane of a soluble polymer material.

The present invention relates to a delivery device for zero-orderrelease, i.e. at constant release rate, of an active principle in afluid phase wherein the active principle is either inherently soluble orcan be solubilized.

This constant release rate regimen is described mathematically by theequation

    dQ/dt=constant

where dQ/dt is the release rate, and Q is the amount of substancereleased at time t; or alternatively, in integrated form, as

    Q=constant·t

which shows that the amount of released substance is a linear functionof time.

The term "active principle" is used herein and is intended to beconstrued in its broadest sense as encompassing any chemical substanceor composition which will produce a bioactive or pharmacologicalresponse either at the site of application or at a site remotetherefrom. Insecticides, fertilizers, pharmaceuticals and nutrients are,therefore, included, although not as limiting examples, within theintended meaning of "active principle".

The need of providing means suitable for releasing an active principleaccording to a programmed release scheme into an environment wherein thesubstance is intented to be active has long been felt in severaltechnological sectors such as, e.g. the insecticide, fertilizer,pharmaceutical and health food industries.

The purpose of a programmed release is to achieve selectivity andaccuracy in delivering the optimum dose of bioactive substance to thedesired target, while negligibly affecting non-target sites, atpreselected times and for as long as it may be desirable in order tomaximize effectiveness.

In the agricultural field, one goal, for instance, is that of providingan intense and prolonged insecticidal activity, while minimizingpollution to soil and water. In the pharmacological field, a goal is tomaintain the plasma level of a drug constantly within thetherapeutically effective range for a long time, etc.

Among the controlled release systems and devices, those with constantrelease rate (zero-order release rate) have raised particular interest.

Although the applicability of the device of the present invention is byno means confined to the pharmaceutical field, reference will behereinbelow made for simplicity sake to the administration oftherapeutically effective substances in which the need for providingzero-order release dosage forms is particularly important.

For application in the pharmaceutical field, the device of the presentinvention may take one of the usual dosage forms of administration, suchas tablets, capsules, lozenges, discoids, rectal and vaginalsuppositories, globuli and the like. Several so-called "sustainedrelease" or "slow-release" dosage forms are available in the market.However, the pharmacokinetic analysis of blood samples drawn frompatients who have been administered such forms shows the presence of apeak of plasma concentration (which frequently causes untowardside-effects) followed by a sudden drop of concentration, well below thethreshold of therapeutical effectiveness. At best a certain prolongationof the therapeutical activity may be attained but the drawbacks ofconventional immediate release administration forms are not eliminated.

Recently, an orally administrable indomethacin-containing pharmaceuticalcomposition has been marketed, which releases the active principle atconstant release rate. This novel administration form (OROS) comprises acore tablet containing drugs and excipients, at least one of them havingosmotic activity, which is coated with a semipermeable polymer membrane.The membrane is permeable only to water and is provided with a smallorifice. After ingestion, the osmotic agent in the core causes an influxof water which effects dissolution of the drug. The osmotic pressuredifferential brings about outflow of a saturated drug solution from theorifice. As long as undissolved drug and/or osmotic agent remains, thepressure gradient is constant and the drug delivery rate through theorifice remains zero order.

Because of continued decrease of drug content in the system with time,however, the drug solution becomes less than saturated and the osmoticpressure gradient and the drug delivery rate decline exponentiallytoward zero. The system ceases to function when iso-osmotic conditionsset in.

Although about 70% of the drug content is actually released inzero-order fashion, this system presents the serious drawback to channelthe whole drug solution through the orifice in the membrane.

This extremely specific localization of the release of active principleand its high concentration (saturated drug solution outflow taking placeonly from a practically punctiform area of the OROS tablet) can bringabout, particularly when the active principle is as aggressive asindomethacin, damage to the gastric mucosa areas which are exposed to orare located in the close proximity to the release drug.

The main object of the present invention is to provide a delivery devicefor zero-order release of an active principle which does not present thedrawbacks of the known devices and systems.

According to the present invention, and with reference to FIGS. 1 and 2which are longitudinal cross-sectional views of two embodiments, thedelivery device for zero-order release of an active principle into adissolution fluid therefor comprises a solid matrix-type reservoir 1Aand 1B formed of a polymer material which is insoluble and unswellablein the dissolution fluid. The reservoir is porous, at least a portion ofthe active principle being dispersed in the pores of the reservoir. Thereservoir comprises a tablet formed of a homogeneous mixture of thepolymer material, the active principle, and an additive which is solubleinto the dissolution fluid with negative heat of solution.

A coating uniformly surrounds the reservoir. This coating comprises twomembranes.

The first, release rate-controlling, membrane 2A and 2B is homogeneousand continuously wraps the reservoir and is formed of a film-formingpolymer material insoluble in the dissolution fluid and permeable to thesubstance. The thickness of the first membrane is determined by theequation

    thickness=h=D·S·C.sub.S /R

wherein:

D is the constant of diffusion across the membrane;

S is the surface area through which diffusion occurs;

C_(S) is the saturation concentration of the substance in thedissolution fluid; and

R is the substance release rate.

The second, protective, membrane 3A and 3B is homogeneous andcontinuously wraps the release rate-controlling membrane, the protectivemembrane being formed of a film-forming polymer material soluble in thedissolution fluid.

Particularly relevant for the purposes of the present invention is thethickness, h, of the release rate-controlling membrane. Thickness, h, isdeduced from Fick's law. Fick's law establishes that once steady-stateconditions are attained, the release rate remains constant andindependent of time if a solute is confined within a "reservoir"surrounder by a continuous polymer membrane and the thermodynamicalactivity of the solute is kept constant within the reservoir. When theenergy of the system is the solute diffusion energy across the membrane,Fick's law is represented by

    dQ/dt=R=D·S·C.sub.S /h

Since D, S, C_(S) and h are assumed to remain constant, the amount ofsolute which diffuses across the membrane per time unit is constant,i.e. diffusion occurs according to zero-order kinetics.

The operation of the device of the present invention may be described asfollows.

The dissolution fluid, for example body fluids, first dissolves theprotective membrane and hydrates the release rate-controlling membrane.The dissolution fluid then penetrates inside the solid reservoir anddissolution of the active principle thus begins, either because it isinherently soluble or because its dissolution is promoted by the "insitu" presence of suitable buffer agents, as it will illustrated ingreater detail below. Thereafter, the concentration of the innersolution will reach the saturation value, C_(S). From this moment on solong as the active principle concentration remains equal to C_(S), theamount released from the surface of the delivery rate-controllingmembrane will be directly proportional to the time; i.e. the releasewill be according to zero-order release kinetics. In contrast, the solidreservoir if uncoated would release the active principle proportionallyto the square root of time (Higuchi's law).

It is apparent that in order to maintain as long as possible theconditions determining the zero-order kinetics, it is essential that theactive principle concentration remain substantially equal to C_(S), andthat the pH inside the system, the diffusion coefficient, the surfacearea and thickness of the delivery rate-controlling membrane remainsubstantially constant during the device life-span.

These objects are attained by the present invention through both thesuitable selection of polymer materials for the solid reservoir and thedelivery rate-controlling membrane, and the selection of appropriateadditives, particularly the additives which promote the formation of thechannel network throughout the solid reservoir, buffer the activeprinciple solution, inhibit the solid reservoir swelling, and plasticizethe delivery rate-controlling membrane. Specifically, the qualitativeand quantitative composition of the solid reservoir is mainly governedby the active principle solubility, as it will be apparent by thefollowing detailed description of the various embodiments of theinvention and the respective roles of their components.

SOLID MATRIX-TYPE RESERVOIR

The solid matrix-type reservoir preferably comprises from 3 to 20% byweight of polymer material; from 30 to 90% by weight of activeprinciple; and from 5 to 50% by weight of an additive soluble into thedissolution fluid with negative solution heat.

The polymer material should be unswellable and insoluble in the activeprinciple's dissolution fluid in order to avoid alterations of therelease rate-controlling membrane as by cracking and, for pharmaceuticaldosage forms, also biocompatible. Typical materials include celluloseacetate, high viscosity hydroxypropylmethyl cellulose, cellulose acetatepropionate, ethyl cellulose and polymethacrylates.

The additive soluble in the dissolution fluid with negative heat ofsolution generally is a polyol, including sugars, such as mannitol,dextrose, sorbitol, xylitol and the like. Both the role played by thisadditive and amount thereof are strictly dependent on active principle'ssolubility. However, also an acid, e.g. citric acid, can be used.

When the active principle is soluble in the dissolution fluid, theadditive acts mainly as a plasticizer towards the releaserate-controlling membrane.

The negative heat of solution is an essential property of the additivein order that it can act as plasticizer, avoiding a reservoir volumeincrease and resultant release rate-controlling membrane modification.

When the active principle is sparingly soluble, the additive also playsthe role of promoting the formation of a channel network in the solidreservoir, thus gradually increasing its porosity. Consequently, boththe dissolution process of the active principle and its ease of reachingthe inner surface of the membrane through the channels filled withdissolution fluid are maximized. This contributes to maintaining theactive principle concentration in the solution inside the system equalto the saturation value, C_(S).

When the additive acts solely as plasticizer, it is sufficient that thesolid reservoir contains from about 5 to about 15% by weight of additivewhereas, when it also acts as channeller, the solid reservoir willcontain from about 15 to 50% by weight of additive.

When the active principle is soluble, it itself acts as channeller. Whenthe active principle is sparingly soluble dissolution then is favouredby the presence of the additive additive channeller. In either case, theporosity of the solid reservoir increases as more and more of the activeprinciple dissolves without, however, the outer dimensions of the solidreservoir being thereby affected.

If the active principle's solubility is influenced by the pH of thedissolution liquid, the solid reservoir will conveniently include one ormore suitable buffer agents which will be selected, according tocriteria well-known in this art, depending on the chemico-physicalcharacteristics of the bioactive substance to be solubilized. The systeminner pH consequently will remain substantially constant, againfavouring the uniform dissolution of the active principle. In suchinstances the solid matrix-type reservoir conveniently will contain upto 30% by weight, preferably from 5 to 20% by weight, of the bufferingagent.

RELEASE RATE-CONTROLLING MEMBRANE

The polymer material of the first, release rate-controlling, membranemust be a film-forming polymer which is permeable to the activeprinciple but insoluble in the dissolution fluid. These are essentialprerequisites so that the membrane features, particularly its thicknessand surface area, are not subject to alterations which would in turnaffect the release kinetics of the active principle. The polymer alsomust be biocompatible for pharmaceutical dosage forms.

Suitable polymer material of the release rate-controlling membraneinclude vinyl polymers and copolymers, celluloses cellulose acetate,hydroxy-propylmethylcellulose, cellulose acetate propionate,ethylcellulose, acrylic polymers and copolymers and the like.

In order that the characterizing features of the releaserate-controlling membrane do not vary with time, the plasticizing actionexerted on this membrane by the additive with a negative heat ofsolution contained in the solid reservoir is essential. The releaserate-controlling membrane itself may contain a further plasticizer, e.g.dimethylpolysiloxane or castor oil.

The thickness of the release rate-controlling membrane is determined bythe previously mentioned equation. Generally, the thickness will bebetween 0.04 and 0.01 mm. In practice, the thickness conveniently can beexpressed as milligrams of coating/cm² of surface active area of solidreservoir, a suitable coating corresponding to 4-8 mg/cm².

PROTECTIVE MEMBRANE

The polymer material of the second, protective, membrane must be afilm-forming polymer, easily soluble or dispersable in the dissolutionliquid. Again for pharmaceutical dosage forms, this polymer should bebiocompatible.

Preferably the polymer material of the protective membrane is a solublecellulose derivative, most preferably low viscosityhydroxypropylmethylcellulose.

A portion of the active principle may be incorporated into the polymermaterial of the protective member so as to allow the active principle tobecome immediately available (e.g. in order to rapidly reach thetherapeutically effective plasma level), thereby compensating for thetime lag in the active principle release. This time lag is obviouslyrelated to the time which is necessary for the release rate-controllingmembrane to become hydrated and the proper working equilibriumconditions in the device to be attained. For this purpose from 5 to 20%by weight of the active principle can be incorporated into theprotective membrane.

As previously stated, biocompatible polymer materials will be used forthe manufacture of pharmaceutical dosage forms. The exhausted deliverydevice will, therefore, be easily removed. It also is possible toutilize biodegradable polymers, provided that during the "life" of thedevice (e.g. for at least 10 to 12 hours following oral administration)no noteworthy degradation phenomena occur.

According to an embodiment which is particularly preferred in the caseof an orally administrable pharmaceutical dosage form, the device ofthis invention takes on the shape of a biconvex discoid. FIGS. 1 and 2show the longitudinal cross-sectional views of two such embodiments.

Preferably, the solid matrix-type reservoir of the biconvex discoid hasdiameter comprised between 6 and 16 mm; the bending radius of thespherical segments of the biconvex discoid is from 10 to 18 and thediameter:thickness ratio of the biconvex discoid is from 2 to 5.

In the case the amount of active principle contained in the dosage unitis below about 200 mg, the edges of the opposed spherical segments aresubstantially in mating relationship to each other and the discoidassumes the flat, lenticular shape shown in FIG. 1.

When the amount of active principle exceeds 200 mg/dosage unit, thediscoid takes on the customary shape illustrated in FIG. 2, the discoidcomprising a cylindrical body with the spherical segments above andbelow the cylindrical body.

The present invention also comprises a process for manufacturing thepreviously illustrate device. The process is characterized in that itcomprises the following steps:

(1) Mixing the active principle and the additive soluble in thedissolution fluid with negative heat of solution with a solution of thepolymer material of the solid matrix-type reservoir in an organicsolvent, granulating, drying and adding a lubricant to the driedgranulate;

(2) compressing the mixture of step (1) in a tablet press according toknown techniques at a pressure of 2500-4000 Kg/cm², thus obtaining thesolid matrix-type reservoir;

(3) Applying the release rate-controlling membrane onto the reservoir bycontacting the reservoir of step (2) with a phase containing the firstfilm-forming polymer; and

(4) Applyin the protective membrane onto the reservoir coated with therelease rate-controlling membrane, by contacting the product of step (3)with a phase containing the second film-forming polymer.

Steps (3) and (4) can be carried out in a pan according to knownprocedures. In such cases, the first and second film-forming polymer canbe applied as solutions in organic solvents. Alternatively, steps (3)and (4) can be carried out according to well-known fluid bed techniques.

The device of the present invention presents several advantages over theprior art devices.

At least 70% by weight of the active principle is released withzero-order kinetics, in most cases in 4-8 hours. This can bedemonstrated quantitatively in in vitro models. Moreover, the release ofactive principle takes place over the whole surface of the device, notfrom a limited zone thereof. Consequently, the flux of the activeprinciple solution at the outer surface of the device is slower than theflux presented by prior art devices and the danger of an excessive levelof active principle being released in a limited environment is thusminimized. Unintentional rupture of the release rate-controllingmembrane is extremely unlikely because of the dimensional stability ofthe solid reservoir and membrane and the plasticized condition of thislatter. However, even if the membrane did rupture, this event would notbring about a sudden release ("dose dumping") of active principle wholecontent into the environment. The solid reservoir merely would releasethe active principle at a rate proportional to the square root of time,behaving as controlling modulator of the release.

The active principle solubility also is widely independent of thedissolution fluid pH and possible variations thereof, the pH of thesaturated solution of active principle within the device remainingpractically unchanged.

Finally remarkable stability and strength during handling and storage ofthe device is achieved, in part because of the protective membrane.

The following non-limiting examples illustrate typical delivery devicesaccording to the invention wherein the active principle is an orallyadministrable drug. In these specific examples the device takes on thetypical shape of a biconvex discoid tablet.

EXAMPLE 1 Preparation of tablets of the lysine salt of indomethacin

(a) Preparation of the solid matrix-type reservoirs

In order to prepare 1,000 solid matrix-type reservoirs, the followingamounts of products were used:

Lysine salt of indomethacin (active principle): 100 g;

Cellulose acetate propionate (average molecular weight ≃75,000) EastmanKodak, 482-20 type: 10 g;

Disodium phosphate: 80 g;

Mannitol: 70 g;

Talc: 60 g;

Magnesium stearate: 3 g.

The active principle, sodium phosphate, mannitol and talc were fed intoa powder mixer and thoroughly mixed therein until a completelyhomogeneous mixture was obtained.

A solution of the polymer material in 55 ml of 1:1 acetone:isopropanolwas prepared. The previously obtained powder mixture then was wettedwith this solution. The resulting material was granulated through a 800μsieve, dried and then granulated again through a 420μ sieve.

The granulate thus obtained was mixed with magnesium stearate andsubjected to compression by means of recessed punches having diameter of12 mm, at the pressure of 3,000 Kg/cm², thereby producing biconvex,lenticular solid matrix-type reservoirs (see FIG. 1).

The geometrical features of such reservoirs were the following:

diameter: 12 mm;

bending radius of the spherical segments forming the biconvex reservoir:14 mm;

diameter: thickness ratio: 4;

exposed surface area:

area of one spherical segment: 1.15 cm² ;

area of the pair of spherical segments: 2.30 cm² ;

area of the lateral surface: 0.30 cm² ;

overall surface area: 2.60 cm².

(b) Application of the release rate-controlling membrane

In order to apply the drug release rate-controlling membrane, thefollowing products were used:

low permeability acrylic polymer (EUDRAGIT® RS, Rohm Pharma): 4.5 g;

high permeability acrylic polymer (EUDRAGIT® RL, Rohm Pharma): 18.2 g;

castor oil: 0.6 g;

acetone: 110 ml;

isopropanol: 110 ml.

The release rate-controlling membrane was applied in a pan by sprayingthe polymer solution in short bursts followed by drying intervals withcold air.

The thickness of the release rate-controlling membrane was 0.06 mm,corresponding to 5.4 mg of coating/cm² of surface area of biconvex solidmatrix-type reservoir.

(c) Application of the protective membrane

In order to apply the protective membrane, the following products wereused:

hydroxypropyl methyl cellulose (Pharmacoat 606, Shin Etsu Chemical): 3.0g

titanium dioxide: 1.0 g;

magnesium carbonate: 2.5 g;

indomethacin lysinate: 5.0 g;

solvent mixture (acetone:isopropanol 1:1): 88 ml.

The polymer solution for applying the protective membrane was applied ina pan onto the solid matrix-type reservoirs coated with the releaserate-controlling membrane from the previous step.

In the polymer solution for applying the protective membrane, 10% byweight of the total active principle was added. The kinetics features ofthe indomethacin lysinate release were determined both in "in vitro"models and "in vivo".

"IN VITRO" MODEL

"In vitro" experiments were carried out both on (i) the uncoated solidmatrix-type reservoirs, and (ii) the finished devices; i.e., on thereservoirs coated both with the release rate-controlling membrane andwith the protective membrane loaded with a portion of the activeprinciple which is desired to be immediately available.

To carry out such experiments, a USP XXI "paddle" apparatus was usedwith distilled water at 37° C. as the dissolution medium.

The results were as follows:

A--Indomethacin lysinate release from the solid matrix-type reservoir:

    ______________________________________                                        Time (min.)                                                                              Total drug released (mg)                                                                       Rate (mg/hr)                                      ______________________________________                                        30         20               40                                                60         54               54                                                90         65               43                                                120        75               37.5                                              ______________________________________                                    

B--Indomethacin lysinate release from the solid matrix-type reservoircoated with both the release rate-controlling membrane and protectivemembrane loaded with a portion of the drug:

    ______________________________________                                        Time (hours)                                                                             Total drug released (mg)                                                                       Rate (mg/hr)                                      ______________________________________                                        1          14               14                                                2          25               12.5                                              3          40               13.3                                              4          57               14.25                                             5          77               15.4                                              6          93               15.5                                              ______________________________________                                    

The foregoing results demonstrate that the drug is wholly released fromthe solid matrix-type reservoir in about 5 hours. After the releaserate-controlling membrane is applied, the release rate "in vitro"remains substantially constant through the sixth hour.

"IN VIVO" EXPERIMENTS

A healthy volunteer was administered the same device. The followingplasma levels of active principle were detected.

    ______________________________________                                        Time (hours)   mcg/ml                                                         ______________________________________                                        1              1.6                                                            2              2.5                                                            5              3.2                                                            8              1.5                                                            12             1.1                                                            24             0.8                                                            ______________________________________                                    

EXAMPLE 2 Preparation of tablets of methisoprinol

(a) Preparation of the solid matrix-type reservoirs

In order to prepare 1,000 solid matrix-type reservoirs, the followingamounts of products were used:

methisoprinol (active principle): 500 g;

cellulose acetate propionate (as in Example 1): 25.0 g;

mannitol: 10 g;

magnesium stearate: 8.0 g.

Compounding, granulation and compression procedures as in Example 1.

The geometrical features of the solid matrix-type reservoirs thusobtained (see FIG. 2) were identical to those of the embodiment inExample 1, except that the area of the side wall was 1.32 cm², totalarea was 3.62 cm² and the diameter: thickness ratio was 2.

(b) Application of the release rate-controlling membrane

Solution of polymer material and application procedures as in Example 1.The membrane thickness was 0.07 mm, corresponding to 6 mg of coating/cm²surface area of solid reservoir.

(c) Application of the protective membrane

The same procedures as those of Example 1 were followed, except that noactive principle was loaded in the protective membrane.

"IN VITRO" MODEL

Procedures and apparatus as in Example 1.

A--Methisoprinol release from the solid matrix-type reservoir:

    ______________________________________                                        Time (min.) Total drug released (mg)                                          ______________________________________                                        30          225                                                               60          312                                                               90          365                                                               120         405                                                               ______________________________________                                    

B--Methisoprinol release from the solid matrix-type reservoir coatedwith both the release rate-controlling membrane and the protectivemembrane:

    ______________________________________                                        Time (hours) Total drug released (mg)                                         ______________________________________                                        1             53                                                              2            115                                                              3            173                                                              4            223                                                              5            273                                                              6            315                                                              7            357                                                              ______________________________________                                    

EXAMPLE 3 Preparation of tablets of acetyl L-carnitine chloride

(a) Preparation of the solid matrix-type reservoirs

In order to prepare 1,000 solid matrix-type reservoirs, the followingamounts of products were used:

acetyl L-carnitine (active principle): 500 g;

cellulose acetate propionate (as in Example 1): 40 g;

mannitol: 50 g;

talc: 15 g;

magnesium stearate: 10 g.

Compounding, granulation and compression procedures as in Example 1,except that a pressure of 4000 kg/cm² was used.

Geometrical features of solid reservoirs (see FIG. 2) as in Example 2.

(b) Application of the release rate-controlling membrane

Solution of polymer material and application procedures as in Example 1.The membrane thickness was 0.08 mm, corresponding to 6.5 mg ofcoating/cm² surface area of solid reservoir.

(c) Application of the protective membrane

The same procedures as those of Example 1 were followed, except that noactive principle was loaded in the protective membrane.

"IN VITRO" MODEL

Procedures and apparatus as in Example 1.

A--Acetyl L-carnitine release from the solid matrix-type reservoir:

    ______________________________________                                        Time (min.) Total drug released (mg)                                          ______________________________________                                        30          158                                                               60          242                                                               90          335                                                               120         395                                                               ______________________________________                                    

B--Acetyl L-carnitine release from the solid matrix-type reservoircoated with both the release rate-controlling membrane and theprotective membrane.

    ______________________________________                                        Time (hours) Total drug released (mg)                                         ______________________________________                                        1             60                                                              2            135                                                              3            210                                                              4            280                                                              5            348                                                              6            411                                                              ______________________________________                                    

EXAMPLE 4 Preparation of tablets of clometacin lysinate

(a) Preparation of the solid matrix-type reservoirs

In order to prepare 1,000 solid matrix-type reservoirs, the followingamounts of products were used:

clometacin lysinate, corresponding to clometacin (active principle): 150g;

disodium phosphate: 40 g;

cellulose acetate propionate (as in Example 1): 10 g;

mannitol: 20 g;

talc: 40 g;

magnesium stearate: 5 g.

Compounding, granulation and compression procedures as in Example 1.

Geometrical features of solid reservoirs (see FIG. 1) as in Example 1.

(b) and (c) As in Example 1.

"IN VITRO" MODEL

Procedures and apparatus as in Example 1.

A--Clometacin lysinate release from the solid matrix-type reservoir:

    ______________________________________                                        Time (min.) Total drug released (mg)                                          ______________________________________                                        30           63                                                               60           91                                                               90          105                                                               120         124                                                               ______________________________________                                    

B--Clometacin lysinate from the solid matrix-type reservoir coated withboth the release rate-controlling membrane and protective membraneloaded with a portion of the drug:

    ______________________________________                                        Time (hours) Total drug released (mg)                                         ______________________________________                                        1            15                                                               2            40                                                               3            61                                                               4            78                                                               5            95                                                               6            116                                                              ______________________________________                                    

EXAMPLE 5 Preparation of tablets of trimebutine

(a) Preparation of the solid matrix-type reservoirs

In order to prepare 1,000 solid matrix-type reservoirs, the followingamounts of products were used:

trimebutine, base (active principle): 140 g;

cellulose acetate propionate (as in Example 1): 10 g;

anhydrous citric acid: 100 g;

mannitol: 45 g;

talc: 35 g;

magnesium stearate: 3 g.

Compounding, granulation and compression procedures as in Example 1.

Geometrical features of solid reservoirs (see FIG. 1) as in example 1.

(b) Application of the release rate-controlling membrane

Solution of polymer material and application procedures as in Example 1.The membrane thickness was 0.05 mm, corresponding to 5 mg of coating/cm²surface area of solid reservoir.

(c) Application of the protective membrane

The same procedures as those of Example 1 were followed.

"IN VITRO" MODEL

Procedures and apparatus as in Example 1.

A--Trimebutine release from the solid matrix-type reservoir:

    ______________________________________                                        Time (min.) Total drug released (mg)                                          ______________________________________                                        30          20                                                                60          64                                                                90          80                                                                120         105                                                               ______________________________________                                    

B--Trimebutine release from the solid matrix-type reservoir coated withboth the release rate-controlling membrane and protective membraneloaded with a portion of the drug:

    ______________________________________                                        Time (hours) Total drug released (mg)                                         ______________________________________                                        1            18                                                               2            30                                                               3            50                                                               4            67                                                               5            90                                                               6            103                                                              ______________________________________                                    

EXAMPLE 6 Preparation of tablets of trimebutine

Trimebutine tablets according to this invention were also prepared asfollows:

(a) Preparation of the solid matrix-type reservoirs

In order to prepare 1,000 solid matrix-type reservoirs, the followingamounts of products were used:

trimebutine, base: 135 g;

ethylcellulose: 25 g;

anhydrous citric acid: 100 g;

talc: 44 g;

magnesium stearate: 1 g.

Trimebutine, citric acid, talc and 18.0 g of ethylcellulose werethoroughly mixed for 20 minutes.

The mixture was kneaded with 70 ml of a 10% ethylcellulose solution inethylacetate. The resulting mixture was granulated through a 800μ sieve.The granules were dried, mixed with magnesium stearate and pressed bymeans of recessed 12 mm punches at 3,000 kg/cm². Geometrical features ofthe solid reservoirs (see FIG. 1) as in Example 1.

(b) Application of the release rate-controlling membrane

This membrane was applied in a pan by spraying a 6-8% solution of 4:1Eudragit RL/Eudragit RS in 1:1 isopropanol-acetone, containing 1% byweight of castor oil (22 mg of polymer per reservoir were applied).

(c) Application of the protective membrane

A 6% hydroxypropylmethylcellulose solution in isopropanol-CH₂ Cl₂(corresponding to 60-70 mg of polymer per reservoir) was used. Thesolution also contained 15 mg of trimebutine per reservoir.

"IN VITRO" MODEL

The procedures and the apparatus were the same as those of Example 1.

A--Trimebutine release from the solid matrix-type reservoir:

    ______________________________________                                        Time (min.) Total drug released (mg)                                          ______________________________________                                        20          47                                                                40          64.8                                                              60          77.0                                                              80          87.8                                                              100         94.5                                                              180         115                                                               ______________________________________                                    

B--Trimebutine release from the solid matrix-type reservoir coated withboth the release rate-controlling membrane and protective membraneloaded with a portion of the drug:

    ______________________________________                                        Time (hours) Total drug released (mg)                                         ______________________________________                                        0.5           22.5                                                            1             45.0                                                            2             82.5                                                            3            105.0                                                            4            120.0                                                            5            127.5                                                            ______________________________________                                    

EXAMPLE 7 Preparation of diltiazem tablets

(a) Preparation of the solid matrix-type reservoirs

In order to prepare 1,000 solid matrix-type reservoirs, the followingamounts of products were used:

diltiazem HCl (active principle): 120 g;

cellulose acetate propionate (see Ex. 1): 14 g;

mannitol: 20 g;

talc: 183 g;

magnesium stearate: 3 g.

Compounding, granulation and compression procedures as in Example 1:solid reservoirs weighting 340 mg each were obtained; thickness 3.2-3.3mm.

(b) and (c) Application of release rate-controlling membrane (25 mg ofpolymer per reservoir) and protective membrane (no active principleloaded therein) as in Example 6.

"IN VITRO" MODEL

A--Diltiazem release from the solid matrix-type reservoir:

    ______________________________________                                        Time (min)  Total drug released (mg)                                          ______________________________________                                        15          40.0                                                              30          57.6                                                              45          69.6                                                              60          80.4                                                              75          85.2                                                              ______________________________________                                    

B--Diltiazem release from the solid matrix-type reservoir coated withboth the release rate-controlling membrane and protective membrane:

    ______________________________________                                        Time (hours) Total drug released (mg)                                         ______________________________________                                        0.5          14.4                                                             1            29.5                                                             2            67.6                                                             3            89.9                                                             4            102.3                                                            ______________________________________                                    

What is claimed is:
 1. A delivery device which in the presence of adissolution fluid releases a biologically active principle at asubstantially constant rate for an extended period of time, the devicecomprising(a) a reservoir comprising(i) a solid porous matrix ofhomogenous polymeric material which material is insoluble andunswellable in the dissolution fluid, the geometric dimensions of whichremain substantially unchanged over said period of time; (ii) anadditive which is soluble in the dissolution fluid and which has anegative heat of dissolution with respect to said fluid; and (iii) thebiologically active ingredient, said additive and biologically activeingredient being disposed in the pores of said matrix; (b) a firsthomogenous and continuous coating of a film-forming polymer on saidreservoir, said coating maintaining a substantially constant surfacearea and thickness over said period of time, said polymer beinginsoluble in said dissolution fluid with said coating being permeable toboth said fluid and to a solution of said active ingredient in saidfluid, the thickness of said first coating being such as to complysubstantially with the relationship:

    thickness=D×S×C.sub.s /R

in whichD is the diffusion constant of said first coating; S is thesurface area of said first coating; C_(s) is the saturation constant ofthe active principle in the dissolution fluid; and R is the releaserate; and (c) a second homogenous and continuous coating of a afilm-forming polymer material which is soluble in the dissolution fluiddisposed over said first coating.
 2. A device according to claim 1wherein said reservoir includes a buffer.
 3. A device according to claim2 wherein said buffer constitutes up to about 30% by weight of saidmatrix.
 4. A device according to claim 1 wherein said biologicallyactive principle is present in an amount from about 30 to about 90% ofthe weight of said reservoir.
 5. A device according to claim 1 whereinsaid additive which is soluble in the dissolution fluid with a negativeheat of solution is present in an amount of from about 5 to about 50% ofthe weight of said reservoir.
 6. A device according to claim 5 whereinsaid additive is a polyol or an acid.
 7. A device according to claim 6wherein said additive in mannitol, dextrose, sorbitol, or xylitol.
 8. Adevice according to claim 1 wherein said matrix constitutes from about 3to about 20% of said reservoir.
 9. A device according to claim 8 whereinthe polymeric material of said matrix is cellulose acetate, highviscosity hydroxypropylmethyl cellulose, cellulose acetate propionate,ethyl cellulose, or polymethacrylate.
 10. A device according to claim 1wherein said first homogenous and continuous coating is a vinyl polymeror co-polymer, cellulose, cellulose acetate, hydroxypropylmethylcellulose, cellulose acetate propionate, ethyl cellulose, an acrylicpolymer, or an acrylic co-polymer.
 11. A device according to claim 1wherein said second coating is low viscosity hydroxypropylmethylcellulose.
 12. A device according to claim 1 wherein additional activeprinciple is present in said second polymeric coating.
 13. A deviceaccording to claim 1 wherein a plasticizer is present in said firstcoating.
 14. A device according to claim 1 wherein said biologicallyactive principle is an orally administerable drug.
 15. A deviceaccording to claim 14 wherein the outer surface of said reservoir is abiconvex discoid defined by the circular intersection of two opposedspherical segments, the discoid having diameter from 6 to 16 mm, thebending radius of the spherical segments of the biconvex discoid beingcomprised between 10 and 18 mm, the diameter:thickness ratio of thebiconvex discoid being comprised between 2 and
 5. 16. A device accordingto claim 14 wherein said reservoir defines an intermediate cylindricalwall segment and two opposed spherical end segments intersecting saidcylindrical wall segment.